Field of the Invention
[0001] The present invention relates to a new association of active ingredients working
as anesthetic and pre-anesthetic formulated in a composition containing anesthetics
and analgesics especially suitable for use in surgical and pre-surgical procedures
and others which require sedation, tranquilization, chemical restraint and pre-anesthetic
medication.
[0002] More specifically, the present invention relates to a new association comprising
the active ingredients ketamine, midazolam, and tramadol, formulated in true solution
for parenteral use intended for veterinary anesthesia and analgesia. More preferably,
ketamine is the isomer S-ketamine (+).
[0003] The present invention also contemplates an anesthetic drug for veterinary use.
[0004] Several drugs are used as pre-anesthetic medication having as some of its main goals
the reduction of the dose of the inducing agent and the production of a preventive
analgesia. Among those drugs are dissociative agents, benzodiazepines and opioids.
[0005] Ketamine is a phencyclidine derivative that acts by inhibition mechanisms of the
corticothalamic system and concomitant activation of the limbic system. It produces
dissociative-type anesthesia of short duration, characterized by the absence of responses
to nociceptive stimuli and maintenance of protective reflexes. Ketamine, by concomitantly
increasing the heart rate, cardiac output, blood pressure, left ventricular work and
myocardial oxygen consumption, has been associated to sedatives or tranquilizers that
eliminate or minimize such effects. Currently, the availability of the isomer S-ketamine
(+) aroused great interest since it shows power two times greater than the racemic
mixture, but a lesser amount of drug is required to produce the same analgesic effects
with lower incidence of adverse effects than the racemic formulation, decreasing the
severity of ischemic brain lesions by different mechanisms.
[0006] Ketamine, enantiomers and salts thereof and processes for their preparation are referenced
and disclosed in
U.S. Patent 6,743,949, corresponding to Brazilian Patent Application
PI 0002693-0 still unexamined, which are incorporated herein by reference.
[0007] The benzodiazepines exhibit anxiolytic, tranquilizers, hypnotics and muscle relaxant
effects causing amnesia and psychomotor changes and acting primarily on the limbic
system. It reduces the functional activity of the hypothalamus and the cortex through
the potentiation of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter
of the central nervous system. Diazepam and midazolam are the two most commonly used
agents accordingly, being midazolam a drug of shorter half-life than diazepam and
with greater hypnotic potency.
[0008] Tramadol is a synthetic analogue of codeine and has analgesia compared to the one
produced by morphine when administered at equipotent doses. Its use in veterinary
medicine is still very limited, but recent research demonstrates its efficacy and
safety in dogs. For example, at a dose of 2 mg/kg intravenously (slow), in a prophylactic
way, tramadol is shown to provide analgesia similar to that produced by morphine after
ovariosalpingohisterectomy in female dogs, reducing the expired concentration of isoflurane
and modulating neuroendocrine response to pain, reducing the peaks of catecholamine
and cortisol.
[0009] Co-administration of ketamine and benzodiazepines represent one of the most widely
used associations for anesthesia and premedication in small animals, providing security,
minimal depressant effects, and rapid recovery from anesthesia.
[0010] However, it is common knowledge in the art that veterinary anesthesiology continuously
aims at pharmacological contention to establish gory treatments or not allowing safe
and durable manipulations, eliminating general anesthesia without changing greatly
the physiological parameters.
Summary of the Invention
[0011] Through the above knowledge and many experiments carried out by Depositor it was
found that the use of ketamine in combination with midazolam and tramadol, according
to the present invention, allows to obtain a satisfactory sedation or anesthesia,
with greater practicality and economy in choosing a safe and effective sedation and
analgesia protocol for pets by the administration of a single product, promoting cardiovascular
stability and lasting sedation and analgesia.
[0012] Particularly, the isomer S-ketamine (+) is preferred due to advantages with respect
to the formulations of racemic ketamine.
[0013] Furthermore, the association according to the present invention provides greater
cardiovascular, biochemistry and hemogasimetric stability, which means proportionately
greater safety in animals during anesthesia or during recovery from the anesthesia,
combined with a better quality of sedation, muscle relaxation and analgesia.
Detailed Description of the Invention
[0014] The present invention therefore aims to provide a new anesthetic association for
veterinary use comprising at least the active compounds ketamine, particularly the
isomer S-ketamine(+) (Compound A), midazolam (Compound B), and tramadol (Compound
C)
[0015] According to the present invention, a new anesthetic association is formulated in
true solution for parenteral use, and is suitable for surgical cases as the agent
of pre-anesthetic medication, providing preoperative sedation in lower doses of general
anesthetics, besides analgesia before, during and after surgery.
[0016] Preferably, but not limited to, the anesthetic combination according to the present
invention comprises the active ingredients ketamine, particularly the isomer ketamine-(S+),
midazolam and tramadol, in the proportions of 10:1:2, respectively, which may be present
in associations as free base or one or more pharmaceutically acceptable salts, such
as, for example, maleates and / or hydrochlorides.
[0017] Yet another objective of the present invention is to provide a new anesthetic composition
comprising as active ingredients at least the compounds ketamine, particularly the
isomer ketamine-(S+), midazolam and tramadol, carriers and adjuvants pharmaceutically
acceptable for veterinary use.
[0018] The active compounds may be present in the composition according to the present invention
as free base or one or more pharmaceutically acceptable salts.
[0019] Thus, in one non-limitative embodiment of the invention, the composition includes
the active ingredient ketamine, particularly the isomer ketamine-S(+) as hydrochloride,
the active ingredient midazolam as maleate and/or hydrochloride and the active ingredient
tramadol as hydrochloride.
[0020] The anesthetic compositions according to the present invention comprise at least
3% w/v of the association of the active ingredients ketamine, particularly the isomer
ketamine-(S+), midazolam and tramadol, and carriers and adjuvants pharmaceutically
acceptable in veterinary medicine.
[0021] Preferably, the anesthetic compositions according to the present invention comprise
the active ingredient ketamine, particularly the isomer ketamine-(S+) in proportions
ranging from 2.5 to 20% w/v, the active ingredient midazolam in proportions ranging
from 0.25 to 2% w/v, the active ingredient tradamol in proportions ranging from 0.25
to 4% w/v, and carriers and adjuvants pharmaceutically acceptable in veterinary medicine.
[0022] The carriers and adjuvants used in the compositions object of the present invention
may be any one or more selected from those pharmaceutically acceptable in veterinary
medicine. However, preferably, it can be used one or more selected from the group
consisting of:
[0023] - Isotonizing agents: inorganic salts of sodium (NaCl), potassium (KCl), sugars such
as dextrose and lactose, polyalcohols such as glycerin, propylene glycol and polyethylene
glycol, which have the function of the adjustment of the osmolarity of the solution
to avoid plasmolysis.
[0024] - Preservatives and/or antimicrobial preservatives: methylparabens, propylparaben,
ethylparabens, benzyl alcohol, benzethonium chloride, benzalkonium chloride, phenols,
cresols, chlorobutanols, thimerosal, phenylmercuric compounds.
[0025] - Antioxidants and /or reducers: bisulfites, sulfites, metabisulfites, thiosulphates,
propyl gallate, NDGA, EDTA, thioureas, monotiossorbitol, citric acid, tartaric acid,
BHT, BHA, ascorbic acid and tocopherols.
[0026] - Cosolvents: pyrrolidones and derivatives thereof, glycols and polyglycols, polyethylene
glycols, triacetin, ethers and esters of fatty acids, alcohols, glycerols and amides.
[0027] As said, besides those mentioned above, other isotonizing, preservatives, antioxidants,
cosolvents, as well as other carriers and adjuvants may also be formulated together
with the ingredients of the anesthetic association object of the present invention.
[0028] Table 1 below, which should not be construed as limiting for the purposes of the
present invention, illustrates a series of analgesic compositions formulated according
to the teachings above.
TABLE 1
Compound A |
Compound B |
Compound C |
Inert |
10% w/v |
1% w/v |
2% w/v |
87% w/v |
5% w/v |
0.5% w/v |
1% w/v |
93.5% w/v |
2.5% w/v |
0.25% w/v |
0.5% w/v |
96.75% w/v |
15% w/v |
1.5% w/v |
3% w/v |
80.5% w/v |
20% w/v |
2% w/v |
4% w/v |
74% w/v |
Compound A = ketamine, particularly the isomer ketamine-(S+)
Compound B = midazolam
Compound C = tramadol |
[0029] The invention also relates to an anesthetic drug parenterally administrated, preferably
intramuscularly, containing sufficient amounts of anesthetic association so as to
provide the animal with dosages of the active ingredients ketamine, particularly the
isomer ketamine-(S+) (Compound A) ranging from 5.0 to 50.0 mg/kg of body weight, midazolam
(Compound B) ranging from 0.5 to 5.0 mg/kg of body weight and tramadol (Compound c)
ranging from 1.0 to 10, 0 mg/kg of body weight. Preferably, the dosage should guarantee
the delivery of 10 mg/kg of body weight of Compound A, 1 mg/kg of body weight of Compound
B and 2 mg/kg of body weight of Compound C.
[0030] Yet according to an important aspect of the present invention, the administration
intramuscularly of a composition comprising as active ingredients 100 mg/ml of ketamine,
particularly the isomer ketamine-S(+), 10 mg/ml of midazolam and 20 mg/mL of tramadol,
would be indicated for animals in the following situations:
[0031] a) as a single agent of the pre-anesthetic medication in the volume of 1 ml per each
10 kg of body weight, intramuscularly, thus reducing the dose of the inducing agent
and the requirement of general anesthetics;
[0032] b) as a sedative for diagnostic tests (X-rays, ultrasound, biopsies, material collection);
[0033] c) as a sedative for performing minimally invasive procedures such as cleaning wounds,
changing dressings, small skin sutures associated with local anesthetics, placement
and removal of bandages and splints;
[0034] d) as a pre-emptive analgesia, reducing the requirement of analgesics trans and postoperative;
[0035] e) as a commonly used sedative for clinical, diagnostic or laboratory examinations
in excited and/or aggressive animals;
[0036] f) associated with spinal anesthesia for carrying out minor surgical interventions
such as orchiectomy, skin sutures, wound debridement, among others.
Experimental Tests
[0037] Several experimental studies of pharmacological evaluation of the anesthetic association
according to the present invention were conducted in comparison to a marketed product
whose active ingredient is an association of tiletamine and zolazepam.
[0038] The studies were conducted with female cats after pre-anesthetic medication with
medication of the prior art tiletamine/zolazepam (GZTL) and with the drug of the present
invention ketamine/midazolam/tramadol (GMCT), and subjected to continuous infusion
of propofol in 1% microemulsion to perform ovariosalpingohisterectomy. These studies
measured the mean values and standard deviation of heart rate (HR), respiratory rate
(RR), rectal temperature (RT), systolic blood pressure (SBP), mean (MAP) and diastolic
(DBP), glucose and blood gas analysis (arterial pressure of CO2 - PaCO2, arterial
pressure of 02 - Pa02, hydrogen potential - pH, bicarbonate ions - HC03-, CO2 concentration
at the end of expiration - EtCO2 and base excess - EB). The results were tabulated
and shown in Figures 1 to 15 hereinafter discussed.
[0039] The results of the moments M2 and M3 present in the study methodology are shown in
the graphs only in M3 because in the assessments both moments ended up being assessed
together. Thus, said graphs show that:
Figure 1:
[0040] The FC in the Invention Group did not change statistically in relation to the baseline
during the study. However, in the Prior Art Group the FC has raised 15 minutes after
pre-anesthetic medication (M1), differing both from the baseline and between groups
(greater stability in the FC in the Invention Group).
Figure 2:
[0041] Both in the Invention Group and in the Prior Art Group there was statistical difference
for the FR from M1 compared to the baseline, indicating a decrease caused by the administration
of the Invention and the Prior Art, respectively. Between groups, during the same
experimental time, there was no statistical difference. By viewing the graph, the
Invention Group showed a lower decrease of the FR values, as well as improved stability
during the evaluation period.
Figure 3:
[0042] In the Invention Group there was an increase of the SBP compared to the baseline
in M1, indicating an increase in the SBP, and in the Prior Art Group there was an
increase in the SBP after M3 compared to the baseline, indicating an increase in pressure
caused after the anesthetic induction and not after the PAM. In the evaluation between
groups, there was a difference in M1, with greater pressure in the Invention Group
compared to the Prior Art Group (caused by the administration of the Invention).
Figure 4:
[0043] In the Invention Group, PAM was greater from M1 (compared to the baseline), indicating
that the administration of the Invention increased PAM of the animals. For the Prior
Art Group there was an increase of PAM from M2, indicating an increase in MAP caused
after the anesthetic induction. There was no difference among the groups, indicating
a similar increase in the pressure between them.
Figure 5:
[0044] In the Invention Group there was no increase of PAD after M1 compared to the baseline,
indicating an increase in PAD after the administration of the Invention. For the Prior
Art Group there was no difference of PAD compared to the baseline. There was no difference
in DBP among the groups. The group receiving the Invention showed increased arterial
pressures from M1, indicating an increase of it caused by the administration of the
Invention. There is evidence that ketamine has direct adrenergic effect by directly
binding to α and β-adrenergic receptors. These observations suggest that the sympathomimetic
effect of ketamine is due to the combination of sympathetic nervous system stimulation
centrally mediated as a possible effect of ketamine on blocking the reuptake of catecholamines,
causing it to increase the blood pressure after its administration.
Figure 6:
[0045] For the Invention Group there was no difference of rectal temperature during the
procedure. In the Prior Art Group there was no difference compared to the baseline
from M3 (moment of aperture of the abdominal cavity). There were differences between
groups only in M3, namely, smaller variation and less decrease of body temperature
of the animals receiving the Invention.
Figure 7:
[0046] In both groups there was no difference between the times within the same group. Among
groups, at the same moment, room temperature was statistically lower in the Invention
Group between M0 and M8, except in M5. Despite the difference in room temperature,
the animals that had received the Invention showed higher average body temperature
during the procedure, namely, higher thermal stability.
Figure 8:
[0047] In both groups there was a pH difference compared to the baseline from M2, caused
by anesthetic induction or by supplemental 02 performed during the procedure. There
were differences among groups from the baseline to the last assessment. The groups
had similar pH variation.
Figure 9:
[0048] In the Invention Group there was a difference in PaCO2 (increase) from M1 compared
to the baseline, caused after the administration of the Invention. In the Prior Art
Group there was a difference from M2 (increase) compared to the baseline. There were
differences among the groups in M7, in which the Invention Group remained higher than
the Prior Art Group. Despite the difference among groups, the values remained within
physiological limits.
Figure 10:
[0049] In both groups there was a difference compared to the baseline from M2, caused by
supplemental 02 after the anesthetic induction. There were differences between groups
from the beginning of supplemental 02 in M2. The animals that received the Invention
showed higher values of arterial oxygen pressure during the anesthetic procedure.
Figure 11:
[0050] In the Invention Group there was a difference in M5 compared to the baseline (decrease),
and in the Prior Art Group there was a difference from M2 compared to the baseline
(increase).
Figure 12:
[0051] Despite the variation between moments observed in both groups, i.e., a decrease followed
by an increase in the Invention Group and a decrease in the Prior Art Group. Animals
receiving the Invention showed higher excess values of arterial base compared to the
animals that received the Prior Art throughout the study.
Figure 13:
[0052] Despite the variation observed among treatments during the study, the values obtained
remained within the established as physiological for the species, which is above 95%.
Figure 14:
[0053] There was no statistical difference among the groups at the same moment, as well
as between moments in the same group, indicating similarity of results and stability.
Figure 15:
[0054] There was no statistical difference among the groups at the same moment, as well
as between moments in the same group, indicating similarity of results and stability.
[0055] Thus, the studies showed that the degree of sedation in the Invention Group is considered
optimal in 100% of the animals, whereas in the Prior Art Group this index was achieved
in only 66% of the animals.
[0056] The animals receiving the association of the Invention as a pre-anesthetic medication
(PAM) showed cardiorespiratory and hemogasimetric stability, and a better degree of
sedation compared to the animals that received the association of the Prior Art as
PAM.
1. An anesthetic association for veterinary use, intended for use in surgical, pre-surgical
and other procedures which require sedation, tranquilization, chemical restraint and
pre-anesthetic medication, characterized in that it comprises the association of at least the active compounds ketamine, midazolam
and tramadol.
2. An association according to claim 1, characterized in that the active compounds midazolam and tramadol are present as free base or a pharmaceutically
acceptable salt.
3. An association according to claim 2, characterized in that the pharmaceutically acceptable salt is a maleate, a hydrochloride or mixtures thereof.
4. An association according to any one of claims 1 to 3, characterized in that the compounds ketamine, midazolam and tramadol are present in a ratio of 10:1:2,
respectively.
5. An association according to any one of claims 1 to 4, characterized in that the active compounds ketamine, midazolam and tramadol are formulated in true solution
for parenteral use.
6. An association according to any one of claims 1 to 5, characterized in that the active compound ketamine is the isomer ketamine-(S+).
7. An anesthetic composition for veterinary use, intended for use in surgical, pre-surgical
and other procedures which require sedation, tranquilization, chemical restraint and
pre-anesthetic medication, characterized in that it comprises as active ingredients the association of the compounds ketamine, midazolam
and tramadol in an amount of at least 3% w/v and pharmaceutically acceptable carriers
and adjuvants.
8. A composition according to claim 7, characterized in that the active compounds ketamine, midazolam and tramadol are present in the composition
as free base or one or more pharmaceutically acceptable salt.
9. A composition according to claim 8, characterized in that the active ingredient ketamine is provided as hydrochloride, the active ingredient
midazolam is provided as maleate and/or hydrochloride and the active ingredient tramadol
is provided as hydrochloride.
10. A composition according to claim 7, characterized in that the active ingredient ketamine in proportions ranging from 2.5 to 20% w/v, the active
ingredient midazolam in proportions ranging from 0.25 to 2% w/v, and the active ingredient
tradamol in proportions ranging from 0.5 to 4% w/v.
11. A composition according to any one of claims 7 to 10, characterized in that the active compound ketamine is the isomer ketamine-(S+).
12. A composition according to claim 7, characterized in that the carriers and adjuvants are isotonizing compounds, preservatives, antioxidants
and cosolvents.
13. A composition according to claim 12,
characterized in that the carriers and adjuvants are one or more compounds selected from the group consisting
of:
- isotonizing agents: inorganic salts of sodium (NaCl), potassium (KCl), sugars such
as dextrose and lactose, polyalcohols such as glycerin, propylene glycol and polyethylene
glycol, which have the function of the adjustment of the osmolarity of the solution
to avoid plasmolysis.
- preservatives and/or antimicrobial preservatives: methylparabens, propylparaben,
ethylparabens, benzyl alcohol, benzethonium chloride, benzalkonium chloride, phenols,
cresols, chlorobutanols, thimerosal, phenylmercuric compounds.
- antioxidants and /or reducers: bisulfites, sulfites, metabisulfites, thiosulphates,
propyl gallate, NDGA, EDTA, thioureas, monotiossorbitol, citric acid, tartaric acid,
BHT, BHA, ascorbic acid and tocopherols.
- cosolvents: pyrrolidones and derivatives thereof, glycols and polyglycols, polyethylene
glycols, triacetin, ethers and esters of fatty acids, alcohols, glycerols and amides.
14. An anesthetic drug for veterinary use, intended for use in surgical, pre-surgical
and other procedures which require sedation, tranquilization, chemical restraint and
pre-anesthetic medication, and for parenteral administration characterized in that it comprises sufficient amounts to provide the animal with dosages of the active
ingredients ketamine, ranging from 5.0 to 50.0 mg/kg of body weight, midazolam ranging
from 0.5 to 5.0 mg/kg of body weight and tramadol ranging from 1.0 to 10, 0 mg/kg
of body weight.
15. A drug according to claim 14, characterized in that the dosages ensure the delivery of 10 mg/kg of body weight of ketamine, 1 mg/kg of
body weight of midazolam and 2 mg/kg of body weight of tramadol.
16. A drug according to any one of claims 14 to 15, characterized in that the active compound ketamine is the isomer ketamine-(S+).